Mesothelin is a cell surface glycoprotein with expression normally restricted to mesothelia (peritoneum, pericardium, and pleura). However, mesothelin is significantly overexpressed in a variety of tumor types. Mesothelin interacts with Mucin 16 (MUC16 (also called CA125)), a mucin-like glycoprotein previously identified as an ovarian tumor antigen. MUC16 has an extracellular domain comprising at least 14,000 residues and characterized by tandem repeats of 156 amino acids each, referred to as mucin repeats. (See, e.g., O'Brien et al., Tumour Biol. 22:348-366 (2001); Yin et al., J. Biol. Chem. 276:27371-27375 (2001).) The interaction between mesothelin and MUC16 is thought to play a role in heterotypic cell adhesion and metastasis. (See, e.g., Rump et al., J. Biol. Chem. 279:9190-9198 (2004).)
Mesothelin is synthesized as a 71 kDa precursor protein, the mature portion of which is expressed on the cell surface. That precursor protein is proteolytically cleaved by furin into a 31kDa shed component (referred to as megakaryocyte potentiating factor, or MPF) and a 40 kDa mesothelin component. The latter component may remain associated with the cell surface via a glycosylphosphatidylinisotol (GPI) linkage but may also be shed through a proteolytic mechanism.
There is a need in the art for agents that target mesothelin for the diagnosis and treatment of mesothelin-associated conditions, such as cancer. The invention fulfills that need and provides other benefits.